Blood, 2020
Authors
Elizabeth Bulaeva, Davide Pellacani, Naoto Nakamichi, Colin A Hammond, Philip Beer, Alireza Lorzadeh, Michelle Moksa, Annaick Carles, Mikhail Bilenky, Sylvain Lefort, Jeremy Yeyan Shu, Brian Wilhelm, Andrew Weng, Martin Hirst, Connie J Eaves
Publication Abstract

Hematopoietic clones with leukemogenic mutations arise in healthy people as they age, but progression to acute myeloid leukemia (AML) is rare. Recent evidence suggests that the microenvironment may play an important role in modulating human AML population dynamics. To investigate this concept further, we examined the combined and separate effects of an oncogene (c-MYC) and exposure to IL3, GM-CSF and SCF on the experimental genesis of a human AML in xenografted immunodeficient mice. Initial experiments showed that normal human CD34+ blood cells transduced with a lentiviral MYC vector and then transplanted into immunodeficient mice produced a hierarchically organized, rapidly fatal and serially transplantable blast population, phenotypically and transcriptionally similar to human AML cells, but only in mice producing IL3, GM-CSF and SCF transgenically, or in regular mice in which the cells were exposed to IL3 or GM-CSF delivered using a co-transduction strategy. In their absence, the MYC+ human cells produced a normal repertoire of lymphoid and myeloid progeny in transplanted mice for many months but, upon transfer to secondary mice producing the human cytokines, the MYC+ cells rapidly generated AML. Indistinguishable diseases were also obtained efficiently from both primitive (CD34+CD38-) and late (GMPs) cells. These findings underscore the critical role that these cytokines can play in activating a malignant state in normally differentiating human hematopoietic cells in which MYC expression has been deregulated. They also introduce a robust experimental model of human leukemogenesis to further elucidate key mechanisms involved and test strategies to suppress them.

Cancers, 2020
Authors
Banuelos, Carmen A, Ito, Yusuke, Obst, Jon K, Mawji, Nasrin R, Wang, Jun, Hirayama, Yukiyoshi, Leung, Jacky K, Tam, Teresa, Tien, Amy H, Andersen, Raymond J, Sadar, Marianne D
Publication Abstract
Blocking androgen receptor (AR) transcriptional activity by androgen deprivation therapy (ADT) improves the response to radiotherapy for intermediate and high risk prostate cancer. Unfortunately, ADT, antiandrogens, and abiraterone increase expression of constitutively active splice variants of AR (AR-Vs) which regulate DNA damage repair leading to resistance to radiotherapy. Here we investigate whether blocking the transcriptional activities of full-length AR and AR-Vs with ralaniten leads to enhanced sensitivity to radiotherapy. Combination therapies using ralaniten with ionizing radiation were evaluated for effects on proliferation, colony formation, cell cycle, DNA damage, and Western blot analyses in human prostate cancer cells that express both full-length AR and AR-Vs. Ralaniten and a potent next-generation analog (EPI-7170) decreased expression of DNA repair genes whereas enzalutamide had no effect. FACS analysis revealed a dose-dependent decrease of BrdU incorporation with increased accumulation of γH2AX with a combination of ionizing radiation with ralaniten. An additive inhibitory effect on proliferation of enzalutamide-resistant cells was achieved with a combination of ralaniten compounds with ionizing radiation. Ralaniten and EPI-7170 sensitized prostate cancer cells that express full-length AR and AR-Vs to radiotherapy whereas enzalutamide had no added benefit.

Oncotarget, 2020
Authors
Kelly Yi Ping Liu, Sarah Yuqi Zhu, Denise Brooks, Reanne Bowlby, J Scott Durham, Yussanne Ma, Richard A Moore, Andrew J Mungall, Steven Jones, Catherine F Poh
Publication Abstract

Neck lymph node metastasis (LN+) is one of the most significant prognostic factors affecting 1-in-2 patients diagnosed with oral squamous cell carcinoma (OSCC). The different LN outcomes between clinico-pathologically similar primary tumors suggest underlying molecular signatures that could be associated with the risk of nodal disease development. MicroRNAs (miRNAs)are short non-coding molecules that regulate the expression of their target genes to maintain the balance of cellular processes. A plethora of evidence has indicated that aberrantly expressed miRNAs are involved in cancers with either an antitumor or oncogenic role. In this study, we characterized miRNA expression among OSCC fresh-frozen tumors with known outcomes of nodal disease (82 LN+, 76 LN0). We identified 49 differentially expressed miRNAs in tumors of the LN+ group. Using penalized lasso Cox regression, we identified a group of 10 miRNAs of which expression levels were highly associated with nodal-disease free survival. We further reported a 4-miRNA panel (miR-21-5p, miR-107, miR-1247-3p, and miR-181b-3p) with high accuracy in discriminating LN status, suggesting their potential application as prognostic biomarkers for nodal disease.

Clinical Cancer Research, 2020
Authors
Jenny E Chu, Benny Johnson, Laveniya Kugathasan, Van K Morris, Kanwal Raghav, Lucas Swanson, Howard Lim, Daniel J Renouf, Sharlene Gill, Robert Wolber, Aly Karsan, Scott Kopetz, David F Schaeffer, Jonathan M Loree
Publication Abstract

PURPOSE BRAFV600E mutations portend poor prognosis in metastatic colorectal cancer (mCRC); however, the true prevalence and prognosis are unknown, as unwell patients may not undergo BRAF sequencing. PATIENTS AND METHODS We reviewed a population-based cohort of 1898 patients with CRC that underwent reflexive immunohistochemistry (IHC) mismatch repair (MMR) & BRAFV600E testing. Outcomes among IHC detected BRAFV600E mCRC (BRAFIHC) were compared to patients with next generation sequencing identified BRAFV600E mutated mCRC from two institutions (BRAFNGS) with patients spanning from 2004-2018. RESULTS All-stage population prevalence of BRAFV600E was 12.5% (238/1898) and did not differ between early and metastatic stages (p=0.094). Prevalence among mCRC was 10.6% (61/575), of whom 51 (83.6%) were referred to oncology and 26 (42.6%) had NGS testing. BRAFIHC had worse median overall survival (mOS) than BRAFNGS (5.5 vs 20.4 months, hazard ratio (HR) 2.90, 95% confidence interval (CI) 1.89-4.45, p<0.0001) which persisted in multivariate analysis (p<0.0001). Across a combined NGS and IHC cohort, BRAFV600E tumors with deficient MMR showed worse mOS compared to MMR proficient tumors (8.9 vs 17.2 months, HR 1.46, 95% CI 0.96-2.27, p=0.043). In this combined cohort, first-line progression free survival was 5.9 months, with minimal differences between regimens. Within the population-based cohort, attrition between treatment lines was high with only 60.7% receiving first-line chemotherapy and 26.2% receiving second-line. CONCLUSION BRAFV600E mutated mCRC has a worse prognosis than previously suggested, potentially arising from referral bias for testing. High attrition between lines of therapy suggests efficacious therapies need to be prioritized early for patients to benefit.

Annals Of Translational Medicine, 2020
Authors
Cally J Ho, Sharon M Gorski

Journal Of Medical Genetics, 2020
Authors
Alexandra Roston, Dan Evans, Harinder Gill, Margaret McKinnon, Bertrand Isidor, Benjamin Cogné, Jill Mwenifumbo, Clara van Karnebeek, Jianghong An, Steven J M Jones, Matthew Farrer, Michelle Demos, Mary Connolly, William T Gibson
Publication Abstract

Dysfunction of histone methyltransferases and chromatin modifiers has been implicated in complex neurodevelopmental syndromes and cancers.

Genetics, 2020
Authors
Aleksandar Vujin, Steven J Jones, Monique Zetka
Publication Abstract

DNA double-strand breaks (DSBs) are a particularly lethal form of DNA damage that must be repaired to restore genomic integrity. Canonical non-homologous end joining (NHEJ), is the widely conserved pathway that detects and directly ligates the broken ends to repair the DSB. These events globally require the two proteins that form the Ku ring complex, Ku70 and Ku80, and the terminal ligase Lig4. While the NHEJ pathway in vertebrates is elaborated by more than a dozen factors of varying conservation and is similarly complex in other eukaryotes, the entire known NHEJ toolkit in

Nature Methods, 2020
Authors
Ottar N Bjørnstad, Katriona Shea, Martin Krzywinski, Naomi Altman

Clinical Lymphoma, Myeloma & Leukemia, 2020
Authors
Wasithep Limvorapitak, Jeremy Parker, Curtis Hughesman, Kelly McNeil, Lynda Foltz, Aly Karsan
Publication Abstract

JAK2 V617F mutation is one of the major criteria in the diagnosis of myeloproliferative neoplasms (MPN) and its variant allele fraction (VAF) determines the disease phenotype and outcomes. This study aimed to define characteristics and outcomes of patients with JAK2 V617F VAF < 2% compared to patients with VAF 2%-10%.

Frontiers In Veterinary Science, 2020
Authors
Lauren C Tindale, Waren Baticados, Jun Duan, Michelle Coombe, Agatha Jassem, Patrick Tang, Miguel Uyaguari-Diaz, Richard Moore, Chelsea Himsworth, William Hsiao, Natalie Prystajecky
Publication Abstract

Early virus detection and characterization is key to successful avian influenza virus (AIV) surveillance for the health of humans as well as domestic poultry. We explored a novel sampling approach and molecular strategy using sediment from wetlands and outdoor waterbodies on poultry farms as a population-level proxy of AIV activity in waterfowls. RNA was extracted using the MoBio RNA PowerSoil Total RNA isolation kit with additional chloroform extraction steps to reduce PCR inhibition. AIV matrix protein (MP) gene was detected in 42/345 (12.2%) samples by RT-qPCR; an additional 64 (18.6%) samples showed evidence of amplification below the threshold and were categorized as "suspect positive." Enrichment-based targeted resequencing (TR) identified AIV sequences in 79/345 (22.9%) samples. TR probes were designed for MP, hemagglutinin (HA), and neuraminidase (NA), however PB2 and PA were also identified. Although RT-qPCR and TR only had fair-moderate agreement, RT-qPCR positivity was predictive of TR-positivity both when using only strictly positive RT-qPCR samples (OR = 11.29) and when coding suspect positives as positive (OR = 7.56). This indicates that RT-qPCR could be used as a screening tool to select samples for virus characterization by TR and that future studies should consider RT-qPCR suspect positives to be positive samples for subsequent resequencing when avoiding false negatives is the priority, for instance in a diagnostic test, and to consider suspect positives to be negative samples when cost efficiency over a large number of samples is the priority, for instance in a surveillance program. A total of 13 HA (H1-7, H9-13, H16) and 9 NA (N1-9) subtypes were identified, with a maximum of 8 HA and 8 NA subtypes detected in a single sample. The optimized RNA extraction and targeted resequencing methods provided increased virus detection and subtyping characterization that could be implemented in an AIV surveillance system.

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